1. Field of the Invention
This invention relates to polymeric aminosaccharides, processes for their preparation and their use as antihypercholesterolemic agents. More particularly, this invention relates to polymeric aminosaccharides which are high molecular weight nonabsorbable resins resulting from the crosslinking of monomeric or polymeric aminosaccharides and dialdehydes via Schiff's base formation followed by reductive amination to give non-hydrolyzable linkages.
2. Technical Background and Prior Art
Myocardial infarction, thrombosis, and stroke are the clinical sequalae of the underlying disease process of atherosclerosis. Collectively, these manifestations of Coronary Heart Disease (CHD) are at high levels and constitute the number one cause of death and disability in the United States, [R. I. Levy, Arteriosclerosis, 1, 312-325 (1981)]. Economically this loss is estimated at approximately $60 billion in direct health care costs, lost wages, and decreased productivity [Lipid Research Clinics Program, J. Amer. Med. Assoc., 251, 351-364 (1984)]. Epidemiological studies have established the relationship of elevated plasma cholesterol and the incidence of CHD [W. B. Kannel et al. Ann. Intern. Med., 90, 85-91 (1979) and The Pooling Project Research Group, J. Chron. Dis., 31, 201-306 (1978)]. Moreover, the lipoprotein distribution of plasma cholesterol in low density lipoproteins (LDL-C) and high density lipoproteins (HDL-C) have been positively and negatively correlated with CHD, respectively [W. B. Kannel et al., Circulation, 70, 153-205A (1984)]. These observations have fostered the position that a reduction in plasma total and LDL-C through diet and/or drug therapy may be beneficial in the treatment of CHD.
Recently, several studies have been completed which have tested the efficacy of reducing plasma cholesterol through drug therapy and its impact on CHD [Lipid Research Clinics Program, J. Amer. Med. Assoc. 251, 351-364 (1984), J. F. Brensike, Circulation, 69, 313-324 (1984) and R. I. Levy at al., Circulation, 69, 325-337 (1984)]. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) and the National Heart Lung and Blood Institute, Type II Coronary Intervention Study(NHLBI-CIS) both employed the bile acid sequestrant resin cholestyramine in combination with diet modification to lower circulating cholesterol levels. The results of the LRC-CPPT showed that a reduction in total plasma cholesterol by lowering LDL-C can reduce the incidence of CHD morbidity and mortality in men at risk for CHD [Lipid Research Clinics Program, J. Amer. Med. Assoc. 251, 351-364 (1984)]. The reduction in LDL-C and CHD was enhanced by drug treatment.
Similarly, the NHLBI-CIS results [J. F. Brensike, Circulation, 69, 313-324 (1984) and R. I. Levy et al., Circulation, 69, 325-337 (1984)], demonstrate that an increase in HDL-C and decreases in total and LDL-C are associated with lower CHD progression. These favorable lipid profiles were enhanced by cholestyramine therapy. In combination, these results strongly support the conclusion that bile acid sequestrant therapy is an effective means to retard the progression and clinical manifestations of CHD. This action is due to the favorable influence of the drug on the lipoprotein profile of individuals at risk for CHD.
Cholestyramine, an ion exchange resin, is essentially a styrene polymer containing quaternary ammonium groups crosslinked by divinylbenzene and is covered in U.S. Pat. Nos. 3,499,960 and 3,780,171 amongst others. The mechanism for reducing blood cholesterol levels is through absorption of bile acids in the intestinal tract which prevents the circulation of bile acids. Hepatic cholesterol is thereby converted to bile acid, resulting in increased hepatic clearance and lower cholesterol levels in the blood.
Cholestyramine has a gritty consistency and has an unpleasant odor inherent to aliphatic amines, both of which lead to poor patient compliance. Also, it may cause rash and irritation as well as gastrointestinal distress. In addition, it has the drawback that other drug substances and vitamins are also removed by adsorption.
Thus, there is a need for new products which would be useful in bile acid sequestrant therapy which are less gritty, odorless, and which are generally more palatable with fewer side effects than cholestyramine.